ASCO 2019: Genomic Predictors of Benefit of Docetaxel and Next-Generation Hormonal Therapy in mCRPC

Chicago, IL ( Preclinical data indicate that tumor suppressor gene, DNA damage and/or repair, and androgen receptor (AR) gene alterations may impact the efficacy of castration-resistant prostate cancer (CRPC) AR-targeted and cytotoxic life-prolonging therapies. Predictive genomic biomarkers in mCRPC are evolving and include (i) RB1 aberrations, which are consistently associated with poorer outcomes with next-generation hormonal therapy, (ii) PTEN, which is prognostic and may result in less benefit from next-generation hormonal therapy, but no impact on docetaxel efficacy, (iii) AR amplification, resulting in poor response to next-generation hormonal therapy, and (iv) DNA damage repair alterations, of which the outcome of those treated with next-generation hormonal therapy is unclear. At the ASCO 2019 prostate cancer session, Anis Hamid, MBBS, and colleagues assessed genomic predictors of differential benefit of androgen receptor-targeted therapy and chemotherapy for mCRPC. 

In this study, 157 patients with mCRPC and targeted exome sequencing of biopsies obtained after metastatic diagnosis were identified. Time from next-generation hormonal therapy (abiraterone/enzalutamide)or docetaxel start to clinical/radiographic progression (time to treatment failure) was estimated by Kaplan-Meier method, with censoring at next therapy or last follow-up for non-progressors. 

Among the 103 evaluable patients, 80.1% had bone and/or lymph node-only metastases at mCRPC diagnosis. In total, 84.5% and 59.2% received next-generation hormonal therapy and docetaxel for mCRPC, respectively. Median overall survival was 4.5 years from first mCRPC. The frequency and predictive association of selected recurrently-altered genes are as follows:
PTEN alterations were associated with worse time to treatment failure on next-generation hormonal therapy, but not docetaxel; a similar trend was observed with BRCA2. Biallelic RB1 loss was strongly predictive, conferring significantly shorter time to treatment failure on both next-generation hormonal therapy (HR 1.76, 95% CI 0.96-3.21)and docetaxel (HR 2.30, 95% CI 1.10-4.81):

A score based on presence of tumor PTEN alterations and/or biallelic RB1 alterations was predictive of time to treatment failure on next-generation hormonal therapy (median time to treatment failure of score 0 vs 1 vs 2: 14.7 vs 12 vs 3.8 months; log-rank p=0.003). 

Several conclusions can be drawn from this study:
  1. Compound tumor suppressor variants, driven by biallelic RB1loss present in 12% of tumors, are associated with shorter time to progression on both next-generation hormonal therapy and docetaxel therapy
  2. PTEN loss and TP53 loss compound RB1 loss in driving progression on therapy and shorter survival
  3. BRCA1/BRCA2 alterations were associated with poorer overall survival (OS) but no difference in time to progression on next-generation hormonal therapy or docetaxel
Presented by: Anis Hamid, MBBS, Dana-Farber Cancer Institute, Boston, MA

Co-Authors: Himisha Beltran, Atish Dipankar Choudhury, Christopher Sweeney; Dana-Farber Cancer Institute, Boston, MA; Weill Cornell Medical College, New York, NY; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA